Download H.Delshad MD

H.Delshad M.D
Endocrinologist
Research Institute for Endocrine Sciences
The burden of osteoporosis
►The most common metabolic bone
disease
►The most common cause of Fx. in
older adults
►2 million fracture each year :
• 300,000 hip Fx.
• 547,000 Vert. Fx.
• 135,000 Pelvic Fx.
• 20% end up in nursing homes
• 20% mortality within 1 year of fracture
• 2/3 never return to pre-fracture functional level
Annual incidence of common diseases
Comparative annual incidence of osteoporotic fractures
and other disease end-point in women
2,500,000
2,000,000
-
1,500,000
-
1,000,000
-
2,050,000
425,000
500,000
0
-
370,000
192,000
Osteoporotic
fractures
Stroke
Heart attack
Breast cancer
A huge care gap exists after a fracture
The vast majority of men and women presenting at Canadian hospitals with fragility fractures
are neither screened nor treated for their underlying osteoporosis to prevent future fractures.
Iranian Multicenter Osteoporosis Study > 50 Y
Sample size Lumbar
(F/M=1)
(%)
Booshehr
Mashhad
Shiraz
Tabriz
Tehran
Total
250
250
350
350
350
Femur
neck (%)
8
25
25
20
15
4
4.5
6.5
6
4
F=20%
M=6%
F=5%
M=1%
Osteoporosis: Definition
Osteoporosis is the result of dysregulation of bone remodeling
Osteoporosis: Definition
• Low bone mass
• Microarchitectural
deterioration
• Susceptibility to fracture
Osteoporosis : who is at risk?
Osteoporosis : Risk factors
Osteoporosis : Risk factors
Osteoporosis : Diagnosis
• Osteoporosis is a ‘silent’ condition with
few clinical symptoms and a fracture is
often the first sign.
• Like hypertension and atherosclerosis,
osteoporosis can be defined by an
intermediate outcome , in this case, low
bone mineral density ( BMD ).
Osteoporosis : Clinical signs
•
•
Fracture
●
•
pain
Loss of height
Kyphosis
Respiratory difficulty
Gastrointestinal symptoms ( abdominal pain, hernia, reflux)
Long-term disability
Depression
Indicators of secondary causes of osteoporosis (e.g.
glucocorticoid treatment; GI tract disease such as Crohn’s
disease or Celiac disease; hematological malignancies e.g.
myeloma)
•
•
•
•
•
•
•
Osteoporosis : Diagnosis
• Plain film
• SPA
• DPA
• DEXA : The most common method for measurement of
BMD
• QCT
• US
• MRI
BMD - Who Needs It ?
•All women > 65 years
•Men > 70 years
•Post-menopausal woman with major risk factors
•All individuals > 50 years with history of osteoporotic
fracture
•All individuals on long term steroids
•Men with hypogonadal conditions
•Patients with diseases a/w bone loss and fracture
DEXA Apparatus
DEXA Technology
Detector (detects 2 tissue types - bone and soft tissue)
Patient
Collimator
Photons
(pinhole for pencil beam, slit for fan beam)
X-ray Source
(produces 2 photon energies with different attenuation profiles)
( g/cm2 )
Which Skeletal Sites Should Be
Measured?
Every Patien
• Spine
– L1-L4
• Hip
– Total Proximal Femur
– Femoral Neck
– Trochanter
Some Patients
• Forearm (33% Radius)
– If hip or spine cannot be
measured
– Hyperparathyroidism
– Very obese
Use lowest T-score of these sites
Why measure both spine & hip ?
• Spine-hip discordance
a) Find lower BMD site
• Fracture prediction
a) Spine BMD for spine Fx
b) Hip BMD for hip Fx
• Flexibility in monitoring
Contraindications for spinal BMD
measurement
• Pregnancy
• Recent oral contrast media (2-6 days)
• Recent nuclear medicine test (depends on
isotope used)
• Inability to remain supine on the imaging
table for 5 min without movement
• Spinal deformity or disease , orthopedic
hardware in the lumbar spine
Diagnosis Caveats
• T-score -2.5 or less does not always mean
osteoporosis:
– Example: osteomalacia
• Clinical diagnosis of osteoporosis may be
made with T-score greater than -2.5
– Example: a traumatic vertebral fracture with
T-score equals -1.9
• Low T-score does not identify the cause
and medical evaluation should be
considered:
– Example: celiac disease with malabsorption
Osteoporosis: Laboratory
Osteoporosis: who should be treated
Osteoporosis : FRAX
FRAX : Clinical risk factors
FRAX was developed to calculate the 10-year probability of a hip and a major
Osteoporotic Fx.
www.nof.org
or www.shf.ac.uk/FRAX
Ten-year probability of osteoporotic fractures (%) according to BMD T-score at the
femoral neck in women aged 65 years from the UK
Ten-year probability of osteoporotic fractures (%) according to body mass index (BMI)
in women aged 65 years from the UK.
• Adequate intake of dietary calcium (1200 mg/d)
1
2
• Intakes in excess of 1,200 to 1,500 mg per day have limited potential for benefit and
may increase the risk of developing kidney stones or cardiovascular disease
• 800 to 1,000 IU of vitamin D / day for adults age 50 and older
• This intake will bring the average adult’s serum 25(OH)D
concentration to the 30 ng/ml
• Regular weight-bearing exercise
3
4
5
• walking, jogging, Tai-Chi, stair climbing, dancing and tennis,
weight training and other resistive exercises.
•Fall Prevention
• Avoidance of Tobacco use and
excessive alcohol intake
Pharmacotherapy
► Biphosphonates
• Alendronate
• Risedronate
• Ibandronate
• Zoledronic acid
► Calcitonins
►Denosumab
► Eestrogens
► rPTH
► SERMs
► Strontium ranelate
Bisphosphonates
• In bone, bisphosphonates accumulate in the hydroxyapatite mineral phase,
its concentration is increased by a factor of 8 at sites of active bone resorption.
• Bisphosphonates enter osteoclasts and reduce resorption and promotes early cell death.
• Osteoclasts inhibition allows Osteoblasts to slightly increase BMD
1st line therapy for osteoporosis
• Alendronate
• Risedronate
• Ibandronate
• Zoledronic acid
Bisphosphonates :Clinical Evidence
Effect on Lumbar Spine and Femoral Neck BMD in Postmenopausal Women
Alendronate :
Residronate
Ibandronate
Drug
Alendronate
(Fosamax)
Ibandronate
(Bonivia)
Residronate
(Actonel )
Dose
Vertebral
Non-vertebral
For prevention:
Tab.
5mg/d or 35mg/week
5 , 10 , 75 mg For treatment :
10mg/d or 70mg/week
50%
50%
Tab.
2.5 , 150 mg
Amp.
3mg /3ml
50%
-
41 – 49%
36%
70%
25 – 41 %
For treatment :
2.5mg/d or 150mg/mon.
3mg/IV every 3- month
For prevention & treat.
5mg/d ay
Tab.
5 , 35 , 150 mg 35mg/week
150mg/month
Zoledronic Acid
(Reclast)
Decrease Fx risk Over 3-year
Amp.
4 mg
For prevention & treat.
4mg/100 ml IV infusion
Once yearly for treatment
Once every 2-y for preven.
Solution
Zoledronic Acid
( Reclast , Zometa )
$ 1315.71
Powder for Solution
Zoledronic acid has a high binding affinity for hydroxyapatide
Single IV injection of human equivalent dose of zoledronic acid
preserve bone micoartictecure in adult Rats
4 µ/kg
20 µ /kg
100 µ /kgµ
Micro-CT image of adult s Rats proximal tibial metaphysis ( at 32 weeks)
Bisphosphonates :Side Effects
• An acute-phase reaction:
Fever, Myalgia, Bone pain, Influenza-like symptoms , Headache, Arthralgia
and Weakness occurs in 20% of patients after an initial intravenous infusion
of Zoledronic Acid. ( Usually lasts 2 – 3 days )
• Atrial fibrillation :
Zoledronic acid compared with placebo (1.3 percent vs 0.4 percent); the effect
of other bisphosphonates on the incidence of atrial fibrillation is uncertain.
• GI Problems :
Erosive esophagitis, ulceration, and bleeding with daily oral Alendronate or
Residronate , but occur rarely with current (nondaily) regimens.
• Bone Problems:
- Osteonecrosis of the jaw (particularly following IV bisphosphonate for cancer)
- Atypical fractures of the femoral shaft
Osteonecrosis of the jaw
• Approximately 1 in 10,000 to 1 in 100,000
patient-years in patients taking oral
bisphosphonates for osteoporosis
Atypical fracture
A number of recent case reports and series have identified a subgroup of atypical
fractures of the femoral shaft associated with Bisphosphonate use.
A population based study did not support this association. Such a relationship has
not been examined in randomized trials.
Secondary analyses of three large, randomized bisphosphonate trials:
the Fracture Intervention Trial (FIT), the FIT Long-Term Extension (FLEX) trial,
and the Health Outcomes and Reduced Incidence with Zoledronic
Acid Once Yearly (HORIZON) Pivotal Fracture Trial (PFT).
The occurrence of fracture of the subtrochanteric or diaphyseal femur was
very rare, even among women who had been treated with bisphosphonates
for as long as 10 years.
In Sweden, 12,777 women 55 years of age or older sustained a fracture of the femur
in 2008.
1271 women had a subtrochanteric or shaft fracture and 59 patients with atypical fractures.
The relative and absolute risk of atypical fractures associated with bisphosphonate use
was estimated
Although there was a high prevalence of current bisphosphonate use among patients
with atypical fractures, the absolute risk was small.
Conclusions
These population-based nationwide analyses may be reassuring for patients who receive
bisphosphonates.
Calcitonin
• Salmon’s calcitonin :
○ Prolonge action and greater potency compared to mammalian source.
○ Inhibits osteoclast activity and osteoclast lifespan
○ Analgesic effect
○ Not appropriate as 1st line treatment
○ Only use as 2nd or 3rd line treatment in patients who cannot tolerate
bisphosphonates
Calcitonin 200 IU , Intra-nasal spray :
○ 33% reduction in new vertebral fractures
○ 36% reduction in those with history of previous fractures
(PROOF study)
○ No effect on non-vertebral fractures
Nasal Calcitonin :
Effect on lumbar spine BMD ( PROOF : 5 –Y analysis )
PROOF : Prevent Recurrence Of Osteoporotic Fractures
Am J Med , 2000 ; 109: 267- 276
Roles of RANK and RANKL, in Osteoclast Differentiation and Function
•Receptor activator of nuclear
factor-kB (RANK) on the surface of
osteoclast precursor is activated by
the cytokine RANK ligand (RANKL),
which is produced primarily by
osteoblasts.
• This activation,
influences the
differentiation of osteoclasts.
• RANK signaling is also thought to
exert anti-apoptotic effects.
Denosumab
Is a fully human monoclonal antibody to the
receptor activator of nuclear factor-κB ligand
(RANKL) that blocks its binding to RANK,
inhibiting the development and activity of
Osteoclasts, decreasing bone resorption, and
increasing bone density.
FREEDOM Trial :
9.2%
6.0%
As compared with subjects in the placebo group, subjects in the denosumab
group had a relative increase of 9.2% in bone mineral density at the lumbar
spine and 6.0% at the total hip
FREEDOM Trial :
Changes in mean values for serum C-telopeptide of type I collagen (CTX) and serum
pro-collagen type I N-terminal propeptide (PINP) are shown for 160 subjects who were
included in a sub-study of bone-turnover markers
Prolia : Adverse effects
•
•
•
•
•
•
•
•
•
Back pain, muscle pain, pain in the arms or legs
Constipation
Skin inflammation
Severe allergic reactions
Bladder infection
Ear pain
Severe stomach pain
Hypocalcemia
swelling or pain in jaw.
ESTROGEN THERAPY OR HT
Estrogens :
○ Bind to estrogen receptors on bone
○ Block production of cytokines and inhibit bone
resorption and increase BMD
○ Reduced vertebral (33%) and non-vertebral (27%)
fractures
Women Health Initiative ( WHI) :
Large investigation of prevention strategies for cancer ,CVD and osteoporotic fracture
initiated in 1992. It was a very, very large study sponsored by the National Institutes
of Health (NIH), in total enrolling more than 64,000 people in a clinical trial and
100,000 people in an observational study. It is a huge federally funded study.
n=16,608
Postmenopausal women
50 -79 years
n= 8506
Conjugated Estrogen= 0.625 mg/d
MPA = 2.5 mg/d
n=8102
Placebo
HRT component of the WHI
Summary of results at 5.2 years ( early termination)
In post-menopausal women with an intact uterus, HRT was associated with :
Cpolorectal
cancer
-37%
Hip and clinical
Vertebral fractures
-34%
HRT component of the WHI
Summary of results at 5.2 years ( early termination)
In postmenopausal women with an intact uterus, HRT was associated with :
• 29 % increase in CHD events
• 22% increase in total CVD
• 26% increase in invasive breast cancer
• 41% increase in stroke
• 111% increase in venous thrombosis
Current Indications for HT
○ 2nd line treatment due to risk for breast and endometrial cancers
○ Only for post-menopausal women who cannot tolerate non-estrogen medications
○ To be used with the lowest dose possible and for the shortest period of time to
achieve treatment goals
Women,s Health Initiative (WHI)
Risk
Benefit
29% increase CAD
41% increase Stroke
26% increase BC
EARLY STOP
Clear harm : VTE
FRACTURE REDUCTION
COLON CANCER
SERMs
Raloxifene : an alternative to HRT
• Selective estrogen receptor modulators
• Binds to estrogen receptors
• Estrogen agonist activity on bone and circulating lipoproteins
• Estrogen antagonist activity on breast and endometrial tissues
• Increased risk for DVT
• Does not block vasomotor symptoms of menopause
• Increased spine BMD by 2.3% and hip BMD by 2.5% after 3 years
50% reduction in spine fractures
• No effect on hip or other non-vertebral fractures
• 60mg coated tablets taken once daily
• Must be stopped 72 hours prior to and during prolonged
immobilisation
• Decreased absorption with Ampicillin.
Effect of Raloxifene on vertebral fractures after 4 years of treatment
The Multiple Outcomes of Raloxifene Evaluation (MORE) study (6800 subjects)
Ral. 60 mg
Ral. 120 mg
% of women with incident
vertebral fracture
Pbo
Pooled study population
With ≥ 1 previous V. fracture
J Clin Endocrino Metab. 2002, 87 : 3609-3617
Without previous V. fracture
SERMs
Adverse reactions
• Headaches
• Dizziness
• Sweating
• Nausea
• Stuffy nose
• Various pains
• General weakness
Recombinant PTH
Continuous high-dose PTH increases Osteoclast-mediated bone resorption
Mechanism of action of PTH on Osteoblasts
Intermittent low-dose PTH increases bone formation
Recombinant PTH
rPTH is anabolic agent
• Low dose , daily SC injection : enhance bone remodelling
• Bone formation begins within the first month of treatment
• Bone resorption begins after 6 months
• During the first year of treatment bone remodelling is in a
positive balance.
20mcg Teriparatide daily :
• 83% reduction in moderate to severe vertebral fracture in men
• 65% reduction in new vertebral fractures in women
• 53% reduction in non-vertebral fracture risk
Neer et al.
Effect of PTH (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis.
N Engl J Med 2001 ,344: 1434
Teriparatide :
Effect on Lumbar Spine and Hip BMD in postmenopausal women
P< 0.05
Neer et al.
Effect of PTH (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis
N Engl J Med 2001 ,344: 1434
Teriparatide :
(Forteo )
Increases bone mass and improves architecture in ovarectomized monkeys
Control
Teriparatide
Recombinant PTH
The changes in BMD seen with PTH are early and of greater magnitude
than those seen with other treatment and is therefore plays a role in the
treatment of patients with sever established disease who are at
particularly high risk of fragility fractures :
►T score ≤ -3.5 without fracture
►T score ≤ -2.5 with fragility fracture
►Any T score with fragility fracture
Recombinant PTH
• Is well tolerated
• Leg cramps & dizziness
• It caused an increase in the incidence of
osteosarcoma in rats
►Contrindications:
Paget,s , Prior bone radiation, Bone metastases, Hypercalcemia
► The safety and efficacy of Teriparatide has not been demonstrated
beyond two years
►Teriparatide is used for a maximum of two years , follow with
bisphosphonate
Agent
Doseing & Administration
Monthly average cost
Alendronate
Oral Tab. 70 mg / week
$ 87
Ibandronate
Oral Tab. 150 mg / month
$ 100
Ibandronate
IV Injection 3mg /3 month
$ 161
Residronate
Oral Tab. 150 mg / month
$ 100
Zoledronic acid
( Reclast , Zometa )
IV Infusion 5mg / year
$ 1315 / year
Calcitonin
Nasal spray 200 IU/ day
$ 126
Estrogen
Oral Tab. 0.3 mg / day
$ 35
Raloxifen ( Evista )
Oral Tab. 60 mg / day
$ 108
Teriparatide ( Forteo)
Injection 20 µg /day
$ 675
Denosumab ( Prolia )
Injection SC 60 mg/ 6 month
Combination therapy
• Can provide additional small increase in BMD
• The impact of combination therapy on
fracture rates is unknown.
• The added cost and potential side effects
should be weighted against potential gains.
Combination therapy
Conclusions:
•There was no evidence of synergy between parathyroid hormone and Alendronate
• Concurrent use of Aendronate may reduce the anabolic effects of parathyroid
hormone.
• Taken together, these results do not support the concurrent initiation of
Alendronate with parathyroid hormone treatment.
Strontium Ranelate “Protos”
• Act on osteoblasts to increase bone formation
• Increases osteoprotegerin which reduces the number and
activity of osteoclasts to decrease bone resorption
• 41% reduction in vertebral fractures over 3 years
• 43% reduction in hip fractures over 5 years
• 41-59% fracture risk reduction in patients with osteopenia
with or without a prevalent fracture.
• Taken 1 satchet daily at bed-time
Case discussion
CASE DISCUSSION
A 56-year-old woman, with an ankle fracture from
a fall is seen in the emergency department.
She drinks 1 cup of coffee once daily.
She had a cardiology evaluation 4 years ago after
experiencing rapid heartbeat; results were
negative.
She has a 2-year history of rheumatoid arthritis
(RA).
There is no family history of cancer or heart
disease.
Physical Examination and
Laboratory Findings
Height: 152 cm
Weight: 53 kg
BMI: 17.8 kg/m2
HEENT: normal for age
BP: 168/100 mm Hg
Lungs: normal breath sounds
Heart: regular heart rate, no
murmurs, rubs, or gallop
No jugulovenous distention
Abdomen: normal bowel sounds,
no guarding, rebound, rigidity, or
masses
No peripheral edema
Current Medications
Prednisone 5 mg/d for RA
Pravastatin 20 mg/d
HRT
Q1
• In addition to attending to her ankle fracture,
what are the next steps needed for follow-up?
A. BMD testing
B. Complete blood count (CBC),
comprehensive chemistry profile, and
vitamin D levels
C. Evaluation for possible hyperthyroidism
D. Re-evaluation of lipid medication
Q1
A. Recommended. BMD testing is recommended for women who experience a
fracture after age 40 or 50 and any adult with a fragility fracture
B. Recommended. Screening should comprise a complete medical evaluation,
which should include gait, balance, and muscle strength testing; assessment of
risk factors; BMD evaluation; and assessment of the patient’s ability to
understand and comply with treatment intervention. As part of screening, CBC,
serum chemistry, urinary calcium excretion, and serum vitamin D levels should
be included.
C. Recommended. If the practitioner believes there are secondary risk factors for
osteoporosis, thyroid levels should be checked.
D. Optional. There is no fracture-related reason to re-evaluate statin therapy;
however, as part of her medical evaluation, lipid levels should be checked.
osteo
m
5
3
ultiple
Follow-Up Orthopedic Visit
On a follow-up visit for her ankle fracture, She says that she
missed her BMD testing appointment and has not rescheduled.
She has scheduled an appointment with her rheumatologist to
discuss changing her arthritis therapy because she did research
on the Internet and found that glucocorticoids may decrease her
bone density.
Q2
What evaluation(s) is appropriate
at this time?
A. Repeat order for DXA
B. Evaluation of fasting lipid profile
C. Evaluation for markers of bone formation and breakdown
Q2
A. Recommended. She meets the criteria for BMD
testing and should be evaluated by DEXA as soon as
possible.
B. Not recommended. There is no need to re-evaluate
her lipids at this time.
C. Not recommended. Markers of bone turnover may be
predictive of fracture risk reduction after 3 to 6 months
of osteoporosis treatment. However, the role of bone
markers in osteoporosis and fracture risk management is
unclear, as no correlation between changes in bone
marker levels and fracture risk has been established.
1 Month Later
She returns 1 month later to the orthopedist with results from her DXA. Her T-score is
–3.0, indicating osteoporosis . She also reports after consulting with her rheumatologist,
the corticosteroids were discontinued and she was started on disease-modifying
antirheumatic drugs (DMARD) to treat her RA.
Q3
What treatment options may be considered
for her steroid-induced osteoporosis?
A. FDA-approved bisphosphonate
B. Discontinuation of HRT
C. Calcium and vitamin D supplementation
D. Regular swimming exercises
osteo
m
6
4
ultiple
Q3
A. Recommended. The American College of Rheumatology (ACR) recommends
bisphosphonate therapy for individuals with glucocorticoid-induced osteoporosis.
B. Recommended. There is no evidence of added benefit in fracture reduction from
combining HRT with other osteoporosis medications. Concomitant use is not
recommended.
C. Recommended. According to the ACR, supplementation with calcium and vitamin D
should be recommended for patients treated with glucocorticoids and used in conjunction
with bisphosphonates as part of treatment for patients who have had a fracture while
receiving HRT.12
D. Not recommended. Although swimming will not hurt the patient, it has no effect on
building bone, which requires weight-bearing exercises in which the feet and legs bear the
weight, such as walking, jogging, or stair climbing.
She walks 2 miles a day, but may benefit from increasing weight-bearing exercise.
Follow-up
She is prescribed generic alendronate and her
other medications are unchanged.
1 year later.... She has suffered a fracture in
her wrist and returns to the orthopedist for cast
removal. She reports that she discontinued
alendronate because it caused stomach upset and
she stopped taking HRT on her own 6 months ago
when her menopausal symptoms subsided. She
remains very thin, with a BMI of 18 kg/m2.
osteo
5
m
7
4
ultiple
Q4
What are the next steps for her?
A. Start an injectable, such as Teriparatide
B. Urge her to discuss restarting HRT with
her gynecologist
C. Recommend hip protectors to prevent
hip fracture
Q4
A. Recommended. Teriparatide is approved for treatment of osteoporosis
in postmenopausal women and has been shown to reduce fracture risk and
increase lumbar spine bone mass in that population. It is well tolerated and
not associated with stomach upset, which may be good for the patient.
B. Not recommended. There is no evidence of added benefit in fracture
reduction from combining HRT with other osteoporosis medications.
C. Not recommended. Hip protectors have not been shown consistently to
reduce the risk of hip fractures and were not effective in reducing fracture
risk for adults like Rose, who do not live in nursing care facilities.